Longitudinal Lactation Bone Density Study

June 15, 2016 updated by: Mara Horwitz, University of Pittsburgh

"Bone Density and Calcitropic Hormones During Lactation in African-American and Caucasian Women"

Changes in maternal calcium metabolism are necessary during lactation to provide adequate calcium in breast milk for development of the newborn skeleton. The calcium in milk is derived from the maternal skeleton, resulting in significant bone loss, a process thought to be mediated by the actions of parathyroid hormone-related protein (PTHrP) in combination with a decreased estrogen levels. After weaning, bone lost during lactation is rapidly regained.

Differences between African-American and Caucasian bone metabolism are well documented and include higher bone mineral density (BMD), lower risk of fragility fracture, lower 25-hydroxyvitamin D (25(OH) D), and higher PTH in African-Americans compared to Caucasians. Most studies of bone metabolism in lactating women have been done in Caucasians. Because of differences in bone metabolism between African-Americans and Caucasians, we do not know whether African-Americans will have similar findings.

The primary aim of this study is to compare the changes in bone mineral density (BMD) during lactation in African-Americans with those in Caucasians. It is not known whether the loss in BMD during lactation will be the same for both races. African-Americans display skeletal resistance to PTH with short-term infusions and have lower bone resorption, higher BMD and lower fracture risk than Caucasians. A recent study by our group indicated that lactating African-American mothers had slightly lower bone resorption but quantitatively similar bone formation compared to Caucasians. However, there was a significant increase of 2-3 fold in markers of bone formation and resorption in both groups. Therefore, it is currently not known whether the loss in BMD during lactation will be the same for both races. Primary outcome measures in this study will include spine, hip and radius BMD by Dual X-Ray Absorbiometry (DXA)Scans during lactation (at 2,12 and 24 weeks postpartum or at weaning if prior to 24 weeks postpartum, and six months after weaning (+1 week). This longitudinal protocol will distinguish between two hypotheses. Either: a) as measured by BMD, bone loss in African-Americans during lactation will be equal to that in Caucasians, and skeletal recovery will be the same or possibly accelerated compared to Caucasians; or, b) African-Americans will be resistant to bone loss during lactation compared to Caucasians because of resistance to Parathyroid Hormone-related Protein (PTHrP).

Study Overview

Status

Completed

Conditions

Detailed Description

Pregnancy and lactation are both states of altered maternal calcium metabolism. Maternal calcium mobilization is essential in the provision of an adequate calcium supply to the developing fetus and infant. During pregnancy approximately 30 grams of calcium is required for fetal skeletal development. The extra calcium is derived mostly from increased maternal intestinal absorption, mediated by 1,25 dihydroxyvitamin D (1). During lactation, it is estimated that 600-1000 ml of milk are produced daily with a net maternal calcium loss of 200-400 mg per day (2,3). This calcium is derived from the maternal skeleton, resulting in bone loss of as much as 10% of trabecular bone with serial bone density measurements (3). Demineralization is thought to be mediated predominantly by the actions of parathyroid hormone-related protein (PTHrP) in combination with a suppressed estrogen state. Interestingly, this state rapidly reverses itself with weaning (4,5). Several studies have shown that initial PTHrP measurements are significantly higher in lactating women(3). PTHrP in lactation is produced in high amounts by the mammary gland. Once in the circulation, PTHrP increases bone resorption from the maternal skeleton and increases calcium resorption at the level of the kidney (5,6,27). PTHrP levels have been found to be elevated as much as 10,000 fold in milk as compared with maternal serum, and further increase with suckling (1,6,28). In mouse models, tissue specific-ablation of the PTHrP gene in lactating mammary gland results in decreased bone loss(6).

Given the rapid bone loss reported in lactation, an increase in markers of bone resorption and a decrease in markers of bone formation might be expected. However, a recently published study by our group showed that both markers of bone formation and bone resorption were significantly elevated in lactating Caucasian women (7). This seems unlikely as tight coupling of bone formation and resorption would not result in net calcium mobilization and rapid bone loss during lactation. A more likely explanation is that while bone resorption markers accurately reflect robust osteoclastic bone resorption, the increase in markers of bone formation reflects an increase in immature, partially differentiated pre-osteoblasts that are arrested in development and therefore unable to effectively form new bone. Thus, the rate of resorption exceeds that of formation during lactation and results in a temporary net loss. To support this idea, rat studies have shown that continuous exposure to PTH and PTHrP recruits and initiates osteoblast differentiation, but stops the program prematurely at the preosteoblast transition (8,9,10). This would also suggest a mechanism for the rapid recovery seen after weaning: after withdrawing the PTHrP stimulus, osteoclast-mediated bone resorption would abruptly cease, and previously recruited osteoblast precursors would rapidly complete their differentiation program and restore bone lost during lactation.

African-American bone metabolism differs from Caucasian bone metabolism in several ways. African-Americans display higher bone density and are at lower risk of developing osteoporosis and osteoporotic fracture compared to Caucasians (15-17,29-31). There are may factors which may explain these racial differences in bone metabolism, including altered calcium economy, vitamin D differences, peak attained bone mass, muscle mass and obesity, remodeling rates, bone micro-architecture, hip axis geometry , and other unknown hereditary differences. In particular, it is well established that 25-Hydroxyvitamin D (25-OH D) levels are much lower in African-Americans, due to darker pigmentation resulting in reduced dermal production of 25-OH D as well as reduced intake of vitamin D (11). This hypovitaminosis results in a relative secondary hyperparathyroidism, corroborated by higher levels of PTH and 1,25 dihydroxyvitamin D as well as decreased urinary calcium excretion (12-14). Paradoxically, these higher PTH levels do not correlate with an increase in bone loss. In fact, bone turnover is actually reduced compared to Caucasians, suggesting that African-American bones are more resistant to the effects of PTH, whereas renal sensitivity is maintained or increased (14,18).

The vast majority of studies examining bone metabolism in lactating women have been in Caucasian women. Studies on bone turnover and calcitropic hormones in lactating African-Americans are scarce. Over ten years ago, a study examined markers of bone metabolism in a population of lactating Gambian women (in Gambia) and compared them with a similar cohort of British lactating women (in the UK). The study demonstrated significant increases in older markers of bone formation and resorption during lactation, but also showed higher levels of PTH, 1,25 Vitamin D, serum phosphate, osteocalcin, and alkaline phosphatase in the Gambian lactating population compared with the British lactating population (19). However, Gambian women differ significantly from black women in the developed world in terms of nutrition, both overall calories and calcium intake. Also in contrast to African-Americans, black Gambian women displayed lower BMD than Caucasians. Interestingly, in these studies, Gambian women demonstrated significant losses in whole body and hip BMD during lactation and showed little evidence of bone mass regain after weaning. In fact, Gambian women had continued BMD loss at the hip, in contrast to Caucasian controls.

A recent study by our group (unpublished) explored bone turnover markers and calcium metabolism in African-American lactation. Markers of bone resorption were lower in African-American than Caucasians in non-lactating young women, but increased 2-3 fold in both groups during lactation. Baseline bone formation was comparable in African-Americans and Caucasians, also increasing 2-3 fold in both groups. Fractional excretion of calcium was lower in African-Americans at baseline and remained constant in both groups during lactation. It remains unclear whether bone loss occurs at a similar rate during lactation in the African-American population.

Up to this point, there have been no studies in African-Americans that have utilized bone densitometry to quantitate bone loss and recovery during lactation. This study aims to demonstrate changes in bone density in African-American women during the high bone turnover state of lactation. It will also permit measurements of calcium metabolism, markers of bone formation and resorption, and calcitropic hormones to be compared to bone density changes. We will also look for racial differences in lactating bone metabolism by directly comparing a cohort of African-American lactating women with a similar Caucasian cohort. No prior studies have been done comparing bone mineral density changes in lactating American black and Caucasian women.

Study Type

Observational

Enrollment (Actual)

77

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15213
        • University of Pittsburgh Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years to 45 years (Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

Female

Sampling Method

Non-Probability Sample

Study Population

New mothers will be recruited from UPMC hospital population, primarily Magee Womens Hospital. As this is a study which aims to describe racial differences in bone metabolism during lactation in African-Americans and Caucasians, subjects must identify themselves as belonging to one of these groups.

Description

Inclusion Criteria:

  • 21-45 years old
  • Post-partum after a singleton pregnancy
  • Exclusively breast-feeding (not more than one supplemental bottle of formula per day)
  • African-American or Caucasian by self-identification

Exclusion Criteria:

  • Subjects with cardiac, hypertensive, vascular, renal (serum creatinine of >1.5), pulmonary, endocrine, musculoskeletal, hepatic, hematologic, malignant or rheumatologic disease
  • Fractures or bone surgery within the past 12 months
  • Smokers and subjects with history of significant alcohol or drug use
  • Pregnant women
  • Women who achieved pregnancies with IVF or other hormonal manipulation
  • Women who had significant complications with the most recent pregnancy or who are unable to exclusively breastfeed beginning at birth
  • Subjects on chronic medications other than
  • stable doses of thyroid hormone
  • oral contraceptives
  • vitamin supplements
  • Women on Depo-Provera will be excluded
  • Receiving an investigational drug within 90 days
  • Weight greater than 130 kg
  • Z-score -3.0 or less (hip or spine) on initial DXA

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
African-American Lactating Women
Healthy African-American women who are exclusively breast-feeding.
Caucasian Lactating Women
Healthy Caucasian women who are exclusively breast-feeding.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change from baseline in bone density measurements (BMD)
Time Frame: Change from baseline in BMD at 2,12, 24 weeks postpartum, and six months after weaning.
Primary outcome measures will include spine, hip and radius BMD by DXA at 2, 12, and 24 weeks post-partum and 6 months post-weaning.
Change from baseline in BMD at 2,12, 24 weeks postpartum, and six months after weaning.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change from baseline of bone metabolism measurements
Time Frame: Change from baseline at 2, 12,and 24 weeks postpartum, and six months after weaning.
Bone metabolism measurements include: markers of bone turnover including calcium metabolic parameters such as calcium, phosphorus, fractional excretion of calcium, PTH(1-84), PTHrP, vitamin D metabolites, estradiol, sex hormone binding globulin (SHBG), prolactin, and breast milk calcium levels.
Change from baseline at 2, 12,and 24 weeks postpartum, and six months after weaning.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Pittsburgh

Investigators

  • Principal Investigator: Mara Horwitz, University of Pittsburgh

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2012

Primary Completion (Actual)

September 1, 2015

Study Completion (Actual)

September 1, 2015

Study Registration Dates

First Submitted

June 20, 2012

First Submitted That Met QC Criteria

June 26, 2012

First Posted (Estimate)

June 28, 2012

Study Record Updates

Last Update Posted (Estimate)

June 16, 2016

Last Update Submitted That Met QC Criteria

June 15, 2016

Last Verified

June 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PRO12050600

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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